Background

Donepezil is approved in more than 90 countries around the world for the treatment of mild to moderate Alzheimer's disease, and is approved for the treatment of severe AD in the United States, Japan, Canada, and several other countries. The effect size of donepezil's benefits is small and the drug does not modify the underlying pathophysiology of the disease; even so, this symptomatic treatment has become a mainstay of Alzheimer's therapy in North America.

Donepezil reversibly inhibits acetylcholinesterase (AChE), the enzyme that degrades the neurotransmitter acetylcholine after its release from the presynapse. Donepezil and other acetyl cholinesterase inhibitors increase the availability of the acetylcholine in cholinergic synapses, enhancing cholinergic transmission. Donepezil delays the progressive worsening of cognitive symptoms of Alzheimer's disease.

Donepezil was first approved to be marketed in the United States in 1996, with registration following suit in Canada and the European Union in 1997 and in many other countries shortly thereafter. In 2006/2007, regulatory approval was granted in the United States and Canada, but not in Europe, for its use in the treatment of severe Alzheimer's. Eisai's applications in the United States and Europe for regulatory approval of donepezil for vascular dementia in 2002 and 2003 were rejected and development for this indication stopped, though the drug is being marketed for vascular dementia in India and several other countries. Donepezil is being clinically evaluated in Japan for Down's syndrome and Lewy body dementia.

Donepezil's most common side effects are gastrointestinal, i.e., diarrhea, nausea, and vomiting; dizziness, sleeplessness/fatigue, and urinary incontinence also have been reported. These are known class effects of cholinergic therapies, and often occur primarily at the beginning of treatment.

Besides the standard 5- and 10-mg tablets, a rapidly disintegrating tablet, as well as liquid, oral jelly, and transdermal formulations of donepezil have been developed, but thus far approved only in select countries. In July 2010, the FDA approved a once-daily, sustained-release 23-mg tablet for the treatment of moderate to severe AD; however, this formulation sparked controversy. The advocacy group Public Citizen in 2011 unsuccessfully petitioned the FDA to withdraw it, charging that the formulation was more toxic than the 10-mg tablets without clearly showing greater benefit (e.g., L.A. Times article, Public Citizens Petition). Generic versions of donepezil tablets are available in the United States and many European countries.

Findings

Nearly 230 clinical trials have been conducted thus far with donepezil, a large majority involving Alzheimer's disease. For example, in early stage AD categorized by MMSE between 21 and 26, 10 mg/day of donepezil modestly improved cognition as measured by the ADAS-cog in the first trial exclusively in patients at that stage. Similarly, a separate trial of 296 patients with mild AD showed modest benefit on cognition, particularly on various types of memory (see Seltzer et al., 2004;Seltzer et al., 2002).

In mild to moderate AD, donepezil given at 5 and 10 mg/day modestly improved cognition and functional measures in separate six-month trials of 473 patients and of 818 patients. These and other trials quantified cognition with the ADAS-cog and clinical and global function with the Clinician's Interview-Based Assessment of Change-Plus (CIBIC-plus) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), as well as other measures. A one-year study of the same doses in 286 patients showed similar modest benefits on cognitive and global function, as well as on reducing the burden on caregivers (see, e.g., Rogers et al., 1998; Burns et al., 1999).

The Phase 3, 817-patient AWARE (Aricept WAshout and REchallenge) study looked at continued treatment in patients who did not respond to 5 or 10 mg/day of donepezil for the first six months of treatment. In this study, donepezil was generally well tolerated and had a benefit on memory, as well as a small benefit on activities of daily living and behavioral symptoms in the majority of patients at nine months, including those who did not initially show those benefits (see, e.g., Johannsen et al. 2006). Additional trials in various countries typically evaluated donepezil in 100 to 200 patients and lasted three to six months. In general, most donepezil AD trials have consistently shown modest benefits on cognition, whereas benefits on behavioral symptoms and activities of daily living have been more mixed (see, e.g., news story; Gauthier et al., 2002; Cummings et al., 2006).

Initially, the small effect size of donepezil and other cholinesterase inhibitors created controversy about the cost-effectiveness of this therapy (see Jul 2004 news story and extensive commentary). Since then, several long-term studies—some open-label, some initially blinded but followed by open-label extensions—have shown that donepezil is modestly effective in the long-term treatment of AD. For example, patients who received donepezil for three years had less cognitive decline than placebo-treated patients (see Winblad et al., 2003; 7th Congress of the European Federation of Neurological Societies).Long-term donepezil treatment was reported to delay placement in nursing homes (see Eisei/Pfizer press release).

Pharmacoeconomic studies in the United States and European countries have generally found that donepezil treatment reduces the cost of care. In the United Kingdom, where this debate had called into question coverage of donepezil by its universal health care system, the National Institute for Health and Clinical Excellence (NICE) in 2011 issued a guidance recommending the use of donepezil in the treatment of mild and moderate AD (see, e.g., Fillit et al., 1999; Wimo et al., 2003; NICE guidance; Feldman et al., 2004). Additional pharmacoeconomics studies have since confirmed the cost-effectiveness of donepezil treatment (e.g., Lopez-Bastida et al., 2009).

For severe AD, donepezil has regulatory approval in the United States; trials in other countries are ongoing. In general, studies report modest benefits on cognition, global function, and activities of daily living (see, e.g., Aug 2007 news story; Winblad et al., 2009).

Two Phase 4 trials and one Phase 3 trial evaluated 5 to 10 mg/day of donepezil in more than 1,800 patients with mild cognitive impairment (MCI) in the United States and Canada. Donepezil was shown to slow the progression to AD dementia for about a year, but donepezil does not appear to be under development for an MCI indication (clinicaltrials.gov; clinicaltrials.gov; Petersen et al., 2005; Apr 2005 news story and extensive commentary).

More recent trials focus on evaluating donepezil's potential use in related diseases. In October 2013, Eisai filed for approval of donepezil in Japan for dementia with Lewy bodies (DLB), based on a Phase 3 trial evaluating 5 or 10 mg/day of donepezil in 142 patients and a prior Phase 2 trial in 167 patients with DLB (clinicaltrials.gov; clinicaltrials.gov). Additional trials of donepezil in DLB are ongoing. A previous trial of donepezil in 550 patients with Parkinson's disease dementia (PDD), where dementia develops at least a year after parkinsonian symptoms, missed primary endpoints but showed signals in secondary analyses (Dubois et al., 2012).

In addition, donepezil continues to be studied, particularly the 23-mg tablet and other new formulations. Also under investigation is the drug's effect on other diseases, notably autism. Besides its widespread use in clinical practice, donepezil is frequently used as standard of care in trials testing various investigational drugs as add-on therapy to donepezil. For a listing of donepezil trials, see clinicaltrials.gov.